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Pharmacological Reports : PR Dec 2023Mitragynine (MIT), the primary indole alkaloid of kratom (Mitragyna speciosa), has been associated with addictive and cognitive decline potentials. In acute studies, MIT...
BACKGROUND
Mitragynine (MIT), the primary indole alkaloid of kratom (Mitragyna speciosa), has been associated with addictive and cognitive decline potentials. In acute studies, MIT decreases spatial memory and inhibits hippocampal synaptic transmission in long-term potentiation (LTP). This study investigated the impacts of 14-day MIT treatment on hippocampus synaptic transmission and its possible underlying mechanisms.
METHODS
Under urethane anesthesia, field excitatory post-synaptic potentials (fEPSP) of the hippocampal CA1 region were recorded in the Sprague Dawley (SD) rats that received MIT (1, 5, and 10 mg/kg), morphine (MOR) 5 mg/kg, or vehicle (ip). The effects of the treatments on basal synaptic transmission, paired-pulse facilitation (PPF), and LTP were assessed in the CA1 region. Analysis of the brain's protein expression linked to neuroplasticity was then performed using a western blot.
RESULTS
The baseline synaptic transmission's amplitude was drastically decreased by MIT at 5 and 10 mg/kg doses, although the PPF ratio before TBS remained unchanged, the PPF ratio after TBS was significantly reduced by MIT (10 mg/kg). Strong and persistent inhibition of LTP was generated in the CA1 region by MIT (5 and 10 mg/kg) doses; this effect was not seen in MIT (1 mg/kg) treated rats. In contrast to MIT (1 mg/kg), MIT (5 and 10 mg/kg) significantly raised the extracellular glutamate levels. After exposure to MIT, GluR-1 receptor expression remained unaltered. However, NMDAε2 receptor expression was markedly downregulated. The expression of pCaMKII, pERK, pCREB, BDNF, synaptophysin, PSD-95, Delta fosB, and CDK-5 was significantly downregulated in response to MIT (5 and 10 mg/kg) exposure, while MOR (5 mg/kg) significantly raised synaptophysin and Delta fosB expression.
CONCLUSION
Findings from this work reveal that a smaller dose of MIT (1 mg/kg) poses no risk to hippocampal synaptic transmission. Alteration in neuroplasticity-associated proteins may be a molecular mechanism for MIT (5 and 10 mg/kg)-induced LTP disruption and cognitive impairments. Data from this work posit that MIT acted differently from MOR on neuroplasticity and its underlying mechanisms.
Topics: Rats; Animals; Synaptophysin; Rats, Sprague-Dawley; Hippocampus; Neuronal Plasticity; Long-Term Potentiation; Synaptic Transmission
PubMed: 37924443
DOI: 10.1007/s43440-023-00541-w -
Bosnian Journal of Basic Medical... Aug 2020The two most commonly used immunohistochemical markers for neuroendocrine cells and their tumors are chromogranin A (CgA) and synaptophysin (SPY). CgA is a marker for...
The two most commonly used immunohistochemical markers for neuroendocrine cells and their tumors are chromogranin A (CgA) and synaptophysin (SPY). CgA is a marker for neuroendocrine secretory granules of four pancreatic hormones and gastrin while SPY is a marker for synaptic vesicles in neuroendocrine cells, which release classic neurotransmitters such as acetylcholine and others. CgA is involved in synthesis and secretion of peptide hormones through exocytosis while the function of SPY is elusive. Thirty-five pancreatic neuroendocrine tumors (Pan-NETs) were studied, consisting of 14 insulinomas, 8 gastrinomas, 2 glucagonomas, 6 pancreatic polypeptidomas and 5 non-functioning tumors, and were immunostained for four pancreatic hormones, gastrin, CgA, and SPY. Majority of Pan-NETs were less immunostained for the endocrine hormones and CgA than the normal pancreatic endocrine cells. CgA immunostaining mostly correlates with each hormone staining in non-β-cell tumors, while SPY immunostaining recognizes endocrine cells diffusely in the cytoplasm. CgA immunostaining is less in insulinomas than in non-β-cell tumors, and CgA immunostaining may distinguish CgA-weaker insulinomas from CgA-stronger non-β-cell tumors. CgA immunostaining may be used as an independent marker for biological aggressiveness in non-β-cell Pan-NETs. The serum CgA levels are higher in subjects harboring non-β-cell tumors than those harboring insulinomas, and the serum CgA elevates in parallel to the increasing metastatic tumor mass. Thus, CgA positive immunostaining in Pan-NETs correlates with the elevated serum levels of CgA for diagnosing CgA-positive non-β-cell Pan-NETs and the increasing serum CgA levels indicate increasing metastatic tumor mass.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Synaptophysin
PubMed: 32020844
DOI: 10.17305/bjbms.2020.4632 -
Traffic (Copenhagen, Denmark) Mar 2014Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient... (Review)
Review
Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Recently three proteins have been identified having key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein α-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP-180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. This review will evaluate recent studies to propose working models for the control of sybII traffic by synaptophysin and other Sybtraps (sybII trafficking partners) and suggest how dysfunction in sybII traffic may contribute to human disease.
Topics: Animals; Humans; Monomeric Clathrin Assembly Proteins; Protein Binding; Protein Transport; R-SNARE Proteins; Synaptophysin; alpha-Synuclein
PubMed: 24279465
DOI: 10.1111/tra.12140 -
Annals of Anatomy = Anatomischer... Aug 2022Small clear synaptic-like vesicles fill axon terminals of mechanoreceptors. Their functional significance is controversial and probably includes release of...
BACKGROUND
Small clear synaptic-like vesicles fill axon terminals of mechanoreceptors. Their functional significance is controversial and probably includes release of neurotransmitters from afferent axon terminals. Synaptophysin, a major protein of the synaptic vesicle membrane, is present in presynaptic endings of the central and peripheral nervous systems. It is also expressed in mechanosensory neurons which extend into skin forming sensory corpuscles. Nevertheless, synaptophysin occurrence in these structures has never been investigated.
METHODS
Here we used immunohistochemistry to detect synaptophysin in adult human dorsal root ganglia, cutaneous Meissner and Pacinian corpuscles and Merkel cell-neurite complexes from foetal to elderly period. Moreover, we analyzed whether synaptophysin co-localizes with the mechano-gated protein PIEZO2.
RESULTS
Synaptophysin immunoreactivity was observed in primary sensory neurons (36 ± 6%) covering the entire soma size ranges. Axons of Meissner's and Pacinian corpuscles were positive for synaptophysin from 36 and 12 weeks of estimated gestational age respectively, to 72 years old. Synaptophysin was also detected in Merkel cells (from 14 weeks of estimated gestational age to old age). Additionally in adult skin, synaptophysin and PIEZO2 co-localized in the axon of Meissner and Pacinian corpuscles, Merkel cells as well as in some axons of Merkel cell-neurite complexes.
CONCLUSION
Present results demonstrate that a subpopulation of primary sensory neurons and their axon terminals forming cutaneous sensory corpuscles contain synaptophysin, a typical presynaptic vesicle protein. Although the functional relevance of these findings is unknown it might be related to neurotransmission mechanisms linked to mechanotransduction.
Topics: Adult; Aged; Axons; Biomarkers; Humans; Mechanoreceptors; Mechanotransduction, Cellular; Pacinian Corpuscles; Skin; Synaptophysin
PubMed: 35588932
DOI: 10.1016/j.aanat.2022.151955 -
Genes, Brain, and Behavior Jun 2021The immunomodulatory function of nitric oxide synthase (NOS2) has been extensively studied. However, some behavioral abnormalities caused by its mutations have been...
The immunomodulatory function of nitric oxide synthase (NOS2) has been extensively studied. However, some behavioral abnormalities caused by its mutations have been found in a few rodent studies, of which the molecular mechanism remains elusive. In this research, we generated nos2b gene knockout zebrafish (nos2b ) using CRISPR/Cas9 approach and investigated their behavioral and molecular changes by doing a series of behavioral detections, morphological measurements, and molecular analyses. We found that, compared with nos2b zebrafish, nos2b zebrafish exhibited enhanced motor activity; additionally, nos2b zebrafish were characterized by smaller brain size, abnormal structure of optic tectum, reduced mRNA level of presynaptic synaptophysin and postsynaptic homer1, and altered response to sodium nitroprusside/methylphenidate hydrochloride treatment. These findings will likely contribute to future studies of behavioral regulation.
Topics: Animals; Brain; Gene Deletion; Homer Scaffolding Proteins; Motor Activity; Mutation; Nitric Oxide Synthase; Synaptophysin; Zebrafish; Zebrafish Proteins
PubMed: 33200539
DOI: 10.1111/gbb.12716 -
Molecular Autism 2018Human genetic and genomic studies have supported a strong causal role of deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying...
BACKGROUND
Human genetic and genomic studies have supported a strong causal role of deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human is duplicated in the zebrafish genome and has two homologs, and . Previous studies have reported morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique.
METHODS
CRISPR/Cas9 was applied to generate a loss-of-function mutation ( ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in mutant zebrafish.
RESULTS
zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of deficient zebrafish.
CONCLUSIONS
We generated the first inheritable mutant zebrafish model using CRISPR/Cas9 gene editing approach. zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human function and ASD.
Topics: Animals; Autistic Disorder; CRISPR-Cas Systems; Disease Models, Animal; Homer Scaffolding Proteins; Locomotion; Mutation; Nerve Tissue Proteins; Social Behavior; Synaptophysin; Zebrafish; Zebrafish Proteins
PubMed: 29619162
DOI: 10.1186/s13229-018-0204-x -
BMJ Case Reports Aug 2012Neuroendocrine breast cancer is thought to account for about 1% of all breast cancers. This rare type of breast malignancy is more common in older women and presents as...
Neuroendocrine breast cancer is thought to account for about 1% of all breast cancers. This rare type of breast malignancy is more common in older women and presents as a low-grade, slow-growing cancer. The most definitive markers that indicate neuroendocrine carcinoma are the presence of chromogranin, synaptophysin or neuron-specific enolase, in at least 50% of malignant tumour cells. The authors present a case report of an 83-year-old woman, admitted to their institution with right breast lump. Physical examination, mammography and ultrasonography showed a 2.4 cm nodule, probably a benign lesion (BI-RADS 3). A fine needle aspiration biopsy was performed and revealed proliferative epithelial papillary lesion. She was submitted to excisional biopsy and histology showed endocrine breast cancer well differentiated (G1). Immunohistochemically, tumour cells were positive for synaptophysin. These breast cancers are characterised for their excellent prognosis and conservative treatment is almost always enough to obtain patient cure.
Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Biopsy; Breast Neoplasms; Female; Humans; Mammography; Neuroendocrine Tumors; Synaptophysin
PubMed: 22891013
DOI: 10.1136/bcr.12.2011.5343 -
Annals of Diagnostic Pathology Dec 2023Primary diagnosis of bronchial carcinoids (BC) is always made on biopsies and additional immunohistochemistry (IHC) is often necessary. In the present study we...
Primary diagnosis of bronchial carcinoids (BC) is always made on biopsies and additional immunohistochemistry (IHC) is often necessary. In the present study we investigated the concordance of common diagnostic (synaptophysin, chromogranin, CD56 and INSM-1) and potential prognostic (OTP, CD44, Rb and p16) IHC markers between the preoperative biopsies and resections of in total 64 BCs, 26 typical (41 %) and 38 atypical (59 %) carcinoid tumors. Synaptophysin and chromogranin had 100 % concordance in all resected carcinoids and paired diagnostic biopsies. Synaptophysin was not affected by variable expression in biopsies compared to chromogranin, CD56 and INSM-1. Notably, INSM-1 IHC was false negative in 8 % of biopsies. Of the novel and potential prognostic markers, only CD44 showed 100 % concordance between biopsies and resections, while OTP showed two (4 %) false negative results in paired biopsies. While Rb IHC was false negative in 8 % of biopsies, no strong and diffuse pattern of p16 expression was observed. In this study, most false negative IHC results (85 %, 22/26) were observed in small flexible biopsies. Taken together, our data suggest excellent concordance of synaptophysin and CD44 on the preoperative biopsy samples, while other neuroendocrine markers, Rb and OTP should be interpreted with caution, especially in small biopsies.
Topics: Humans; Synaptophysin; Chromogranins; Biomarkers, Tumor; Immunohistochemistry; Carcinoid Tumor; Biopsy; Lung Neoplasms
PubMed: 37598464
DOI: 10.1016/j.anndiagpath.2023.152181 -
Brain Research Mar 2022Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of...
Temporal lobe epilepsy (TLE) is one of the most common focal pharmacotherapy-resistant epilepsy in adults. Previous studies have shown significantly higher numbers of neurons in the neocortical white matter in TLE patients than in controls. The aim of this work was to investigate whether white matter neurons are part of the neuronal circuitry. Therefore, we studied the distribution and density of synapses in surgically resected neocortical tissue of pharmacotherapy-resistant TLE patients. Neocortical white matter of temporal lobe from non-epileptic patients were used as controls. Synapses and neurons were visualized with immunohistochemistry using antibodies against synaptophysin and NeuN, respectively. The presence of synaptophysin in presynaptic terminals was verified by electron microscopy. Quantification of immunostaining was performed and the data of the patients' cognitive tests as well as clinical records were compared to the density of neurons and synapses. Synaptophysin density in the white matter of TLE patients was significantly higher than in controls. In TLE, a significant correlation was found between synaptophysin immunodensity and density of white matter neurons. Neuronal as well as synaptophysin density significantly correlated with scores of verbal memory of TLE patients. Neurosurgical outcome of TLE patients did not significantly correlate with histological data, although, higher neuronal and synaptophysin densities were observed in patients with favorable post-surgical outcome. Our results suggest that white matter neurons in TLE patients receive substantial synaptic input and indicate that white matter neurons may be integrated in epileptic neuronal networks responsible for the development or maintenance of seizures.
Topics: Drug Resistant Epilepsy; Epilepsy, Temporal Lobe; Humans; Neocortex; Nerve Net; Neurons; Synapses; Synaptophysin; Verbal Learning; White Matter
PubMed: 35041843
DOI: 10.1016/j.brainres.2022.147787 -
Diabetes Aug 2008Pathogenic mechanisms underlying diabetes-induced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the...
OBJECTIVE
Pathogenic mechanisms underlying diabetes-induced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the renin-angiotensin system (RAS) with the synaptic vesicle protein synaptophysin and neuronal activity in the diabetic retina.
RESEARCH DESIGN AND METHODS
C57BL/6 mice with streptozotocin-induced diabetes were treated with the angiotensin II type 1 receptor (AT1R) blocker telimsartan or valsartan, and retinal function was analyzed by electroretinography. Retinal production of the RAS components and phosphorylation of ERK (extracellular-signal regulated kinase) were examined by immunoblotting. Retinal mRNA and protein levels of synaptophysin were measured by quantitative RT-PCR and immunoblot analyses, respectively. In vitro, synaptophysin levels were also evaluated using angiotensin II-stimulated PC12D neuronal cells cultured with or without the inhibition of ERK signaling or the ubiquitin-proteasome system (UPS).
RESULTS
Induction of diabetes led to a significant increase in retinal production of angiotensin II and AT1R together with ERK activation in the downstream of AT1R. AT1R blockade significantly reversed diabetes-induced electroretinography changes and reduction of synaptophysin protein, but not mRNA, levels in the diabetic retina. In agreement with the AT1R-mediated posttranscriptional downregulation of synaptophysin in vivo, in vitro application of angiotensin II to PC12D neuronal cells caused the UPS-mediated degradation of synaptophysin protein via AT1R, which proved to be induced by ERK activation.
CONCLUSIONS
These data indicate the first molecular evidence of the RAS-induced synaptophysin degradation and neuronal dysfunction in the diabetic retina, suggesting the possibility of the AT1R blockade as a novel neuroprotective treatment for diabetic retinopathy.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Cell Line; Diabetes Mellitus, Experimental; Extracellular Signal-Regulated MAP Kinases; Immunoblotting; Mice; Mice, Inbred C57BL; Neurons; Oncogene Protein v-akt; Phosphorylation; RNA Interference; Receptor, Angiotensin, Type 1; Retina; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Signal Transduction; Synaptophysin; Telmisartan; Tetrazoles; Ubiquitination; Valine; Valsartan
PubMed: 18487452
DOI: 10.2337/db07-1281